Project Summary/Abstract Neurodegenerative disorders affect 50% of the population over the age of 85. The strongest risk factor for most neurodegenerative disorders including Alzheimer's disease is aging. Accumulation of mitochondrial DNA (mtDNA) mutations leads to cellular dysfunction, contributes to human aging and can be observed in age-related diseases such as Alzheimer's disease, Parkinson's disease and sarcopenia. Strategies that reduce the mtDNA deleterious mutation load and improve mtDNA quality control are likely to reduce the age-related pathologies of neurodegenerative diseases. We have generated a unique transgenic tool in living Drosophila melanogaster post-mitotic tissue that contains engineered mixed mtDNA deletion mutations (deleterious heteroplasmy model). We aim to generate related systems, and use system biology approaches to identify genes and compounds that lead to suppression or enhancement of the mitochondrial DNA quality control.